Fexofenadine

Fexofenadine

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Systematic (IUPAC) name
(RS)- 2-[4-[1-Hydroxy- 4-[4-(hydroxy- diphenyl- methyl)- 1-piperidyl]butyl]phenyl]- 2-methyl- propanoic acid
Clinical data
Pregnancy category	C (US) B2 (Australia)
Routes of administration	Oral
Legal status
Legal status	Prescription Only (US, UK) OTC (Canada, Australia)
Pharmacokinetic data
Bioavailability	Not yet established
Protein binding	60-70%
Metabolism	Hepatic (5% of dose)
Biological half-life	14.4 hours
Excretion	Feces (~80%) and urine (~11%) as unchanged drug
Identifiers
CAS Number	83799-24-0
ATC code	R06A626 (WHO)
PubChem	CID 3348
DrugBank	APRD00349
ChemSpider	3231
Chemical data
Formula	C32H39NO4
Molar mass	501.656[[]]
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Fexofenadine (Allegra, Telfast, Fastofen, Tilfur, Vifas, Telfexo) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine (brand names include Triludan and Seldane), an antihistamine with potentially serious contraindications. Fexofenadine, like other second and third-generation antihistamines, does not readily cross the blood-brain barrier, and so causes less drowsiness than first-generation histamine-receptor antagonists. It works by being an antagonist to the H₁ receptor.

It has been described as both second-generation and third-generation.

Indications

Fexofenadine is indicated for the relief from physical symptoms associated with seasonal allergic rhinitis and treatment of chronic idiopathic urticaria. It is not a therapeutic drug and does not cure but rather prevents the aggravation of rhinitis and urticaria and reduces the severity of the symptoms providing much relief from repeated sneezing, runny nose, itchy eyes and general body fatigue caused by rhinitis and urticaria.

Dosage

• Chronic idiopathic urticaria: Children 6 months to < 2 years: 15 mg twice daily
• Chronic idiopathic urticaria, seasonal allergic rhinitis:
  • Children 2–11 years: 30 mg twice daily
  • Children ≥ 12 years and Adult: 60 mg twice daily or 180 mg once daily
  • Elderly: Starting dose: 60 mg once daily;

Fexofenadine is not to be taken with fruit juices as this may decrease the absorption of the drug.

Dosage forms

• Suspension: 6 mg/mL (300 mL) [raspberry cream]
• Tablet: 30 mg, 60 mg, 180 mg
• Orally-disintegrating tablet: 30 mg

Common side effects

• Nausea
• Dizziness
• Vomiting
• Weakness
• Drowsiness, sleepiness
• Fatigue
• Diarrhea
• Unusual bowel movements
• Headache
• Aggression
• Fever
• Dry mouth

Overdose

Reports of fexofenadine overdose are infrequent, and because of this, the effects are not well established. No deaths occurred in testing on mice, at 5000 mg/kg, which is one-hundred and ten times the maximum recommended dose for an adult human. Further research shows no deaths in rats at the same concentration, which equates four hundred times the recommended dose in an adult human. Research on humans ranges from a single 800 mg dose, to a twice-daily 690 mg dose for a month, with no clinically significant adverse effects, when compared to a placebo.

History

The older antihistaminic agent terfenadine was found to metabolize into the related carboxylic acid, fexofenadine. Fexofenadine was found to retain all of the biological activity of its parent while giving fewer adverse reactions in patients, so terfenadine was replaced in the market by its metabolite. Fexofenadine was originally synthesized in 1993 by Massachusetts-based biotechnology company Sepracor, which then sold the development rights to Hoechst Marion Roussel (now part of Sanofi-Aventis), and was later approved by the Food and Drug Administration (FDA) in 1996. AMRI holds the patents to the intermediates and production of fexofenadine HCl along with Roussel. Since that time, it has achieved blockbuster drug status with global sales of $1.87B USD in 2004 (with $1.49B USD coming from the United States). AMRI received royalty payments from Aventis that enabled the growth of AMRI.

Synthesis

Fexofenadine may be synthesized as shown from piperidine-4-carboxylate ester and 4-bromophenylacetonitrile.

Chemical synthesis of fexofenadine

To produce the piperidine piece, two phenyl groups are first introduced using a Grignard reaction on the ester, giving a tertiary alcohol. The amine group is then alkylated with a protected aldehyde, then the aldehyde is recovered by deprotection with acid. The remaining piece of the molecule is produced by a double alkylation by iodomethane of the carbanion derived from the nitrile. The nitrile group is then hydrolyzed to a carboxylic acid. The aryl bromide is then lithiated to produce the organolithium compound, which can be coupled with the aldehyde piece to give (after workup) fexofenadine.

References

• Synthesis: Kawai, Stephen H.; Hambalek, Robert J.; Just, George (1994). "A Facile Synthesis of an Oxidation Product of Terfenadine". J. Org. Chem. 59: 2620. doi:10.1021/jo00088a056. 
• Biological effects: Rampe, D; Wible, B; Brown, AM; Dage, RC (1993). "Effects of terfenadine and its metabolites on a delayed rectifier K+ channel cloned from human heart". Mol. Pharmacol. 44 (6): 1240. PMID 8264561. 

External links

• Fexofenadine (UK patient information leaflet)
• Allegra (Fexofenadine Hydrochloride) label and research information
• Sanofi-aventis (Home page)
• Fexofenadine (MedicineNet) (Written by Pharmacists; Reviewed by Doctors)

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